乳腺肿瘤干细胞的研究进展
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摘要
越来越多的研究证明,在乳腺肿瘤中存在一小部分具有自我更新和分化能力的细胞,称之为乳腺肿瘤干细胞,它们在乳腺肿瘤的发生发展和迁移中起到关键作用.乳腺肿瘤干细胞的特性受到一系列细胞内、外因子的调控,包括重要的信号通路、转录因子、非编码RNA和细胞因子,如Hedgehog,Wnt,Notch,Bmi-1,microRNA93,microRNA100和IL6等,均在调控乳腺肿瘤干细胞中起重要作用.另外,肿瘤微环境中的非肿瘤细胞和非细胞成分也是调控乳腺肿瘤干细胞的一个重要因素,如间充质干细胞、巨噬细胞以及细胞因子等.由于乳腺肿瘤干细胞对传统放化疗的不敏感性,结合靶向乳腺肿瘤干细胞的治疗才能更有效地消灭肿瘤.本文就关于乳腺肿瘤干细胞的调控研究及靶向乳腺肿瘤干细胞治疗进行简要综述.
Many studies have shown that a small fraction of cells inside breast tumors possess the ability of self-renewal and differentiation;these cells are called breast cancer stem cells(BCSCs) and play a vital role in tumor progression and metastasis.The characteristics of BCSCs are regulated by multiple intracellular and extracellular factors,including some important signaling pathways(e.g.,sonic hedgehog,Wnt,and Notch),transcription factors(e.g.,Bmi-1),noncoding RNAs(e.g.,miR-93 and miR-100),and cytokines(e.g.,interleukin-6).In addition,the tumor microenvironment,including nonrumor cells(e.g.,mesenchymal stem cells and macrophages) and noncellular components(e.g.,cytokines),is also a key factor regulating BCSCs.Because BCSCs are resistant to conventional therapies,these therapies may be more efficacious when used in combination with BCSC-targeted therapies.In this review,we focus on recent research progress regarding the regulation of BCSCs and BCSC-targeted therapies.
Many studies have shown that a small fraction of cells inside breast tumors possess the ability of self-renewal and differentiation;these cells are called breast cancer stem cells(BCSCs) and play a vital role in tumor progression and metastasis.The characteristics of BCSCs are regulated by multiple intracellular and extracellular factors,including some important signaling pathways(e.g.,sonic hedgehog,Wnt,and Notch),transcription factors(e.g.,Bmi-1),noncoding RNAs(e.g.,miR-93 and miR-100),and cytokines(e.g.,interleukin-6).In addition,the tumor microenvironment,including nonrumor cells(e.g.,mesenchymal stem cells and macrophages) and noncellular components(e.g.,cytokines),is also a key factor regulating BCSCs.Because BCSCs are resistant to conventional therapies,these therapies may be more efficacious when used in combination with BCSC-targeted therapies.In this review,we focus on recent research progress regarding the regulation of BCSCs and BCSC-targeted therapies.
引文
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2 Al-Hajj M,Wicha M S,Benito-Hernandez A,et al.Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci USA,2003,100:3983-3988
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16 Chiba S.Notch signaling in stem cell systems.Stem Cells,2006,24:2437-2447
17 Roy M,Pear W S,Aster J C.The multifaceted role of Notch in cancer.Curr Opin Genets Dev,2007,17:52-59
18 Stylianou S,Clarke R B,BrennanK.Aberrant activation of notch signaling in human breast cancer.Cancer Res,2006,66:1517-1525
19 Miele L,Espinoza I,Pochampally I,et al.Notch signaling:targeting cancer stem cells and epithelial-to-mesenchymal transition Onco Targets Ther,2013,6:1249
20 Zhao D,Mo Y,Li M T,et al.NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells.J Clin Invest,2014,124:5453-5465
21 Bhola N E,Jansen V M,Koch J P,et al.Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notchdependent cancer stem cell population.Cancer Res,2016,76:440-452
22 Liu S,Patel S H,Ginestier C,et al.MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.PLoS Genet,2012,8:e1002751
23 Deng L,Shang L,Bai S,et al.MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.Cancer Res,2014,74:6648-6660
24 Ginestier C,Liu S,Diebel M E,et al.CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts.J Clin Invest,2010,120:485-497
25 Liu S,Ginestier C,Ou S J,et al.Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks.Cancer Res,2011,71:614-624
2 Al-Hajj M,Wicha M S,Benito-Hernandez A,et al.Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci USA,2003,100:3983-3988
3 Liu S,Dontu G,Mantle I D,et al.Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.Cancer Res,2006,66:6063-6071
4 Ginestier C,Hur M H,Charafe-Jauffret E,et al.ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.Cell Stem Cell,2007,1:555-567
5 Liu S,Cong Y,Wang D,et al.Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts.Stem Cell Rep,2014,2:78-91
6 Lewis M T,Veltmaat J M.Next stop,the twilight zone:hedgehog network regulation of mammary gland development.J Mammary Gland Biol Neoplasia,2004,9:165-181
7 Pasca di Magliano M,Hebrok M.Hedgehog signalling in cancer formation and maintenance.Nat Rev Cancer,2003,3:903-911
8 Cohen M M Jr.The hedgehog signaling network.Am J Med Genet,2003,123A:5-28
9苏尚,吴畏.Wnt/b-catenin信号通路对靶基因转录的调控.中国科学:生命科学,2014,44:1029-1042
10 Klaus A,Birchmeier W.Wnt signalling and its impact on development and cancer.Nat Rev Cancer,2008,8:387-398
11 Veeman M T,Axelrod J D,Moon R T.A second canon.Dev Cell,2003,5:367-377
12 Bafico A,Liu G,Goldin L,et al.An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells.Cancer Cell,2004,6:497-506
13 Nakopoulou L,Mylona E,Papadaki I,et al.Study of phospho-β-catenin subcellular distribution in invasive breast carcinomas in relation to their phenotype and the clinical outcome.Mod Pathol,2006,19:556-563
14 Li Y,Welm B,Podsypanina K,et al.Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells.Proc Natl Acad Sci USA,2003,100:15853-15858
15 Dey N,BarwickB G,Moreno C S,et al.Wnt signaling in triple negative breast cancer is associated with metastasis.BMC Cancer,2013,13:537
16 Chiba S.Notch signaling in stem cell systems.Stem Cells,2006,24:2437-2447
17 Roy M,Pear W S,Aster J C.The multifaceted role of Notch in cancer.Curr Opin Genets Dev,2007,17:52-59
18 Stylianou S,Clarke R B,BrennanK.Aberrant activation of notch signaling in human breast cancer.Cancer Res,2006,66:1517-1525
19 Miele L,Espinoza I,Pochampally I,et al.Notch signaling:targeting cancer stem cells and epithelial-to-mesenchymal transition Onco Targets Ther,2013,6:1249
20 Zhao D,Mo Y,Li M T,et al.NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells.J Clin Invest,2014,124:5453-5465
21 Bhola N E,Jansen V M,Koch J P,et al.Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notchdependent cancer stem cell population.Cancer Res,2016,76:440-452
22 Liu S,Patel S H,Ginestier C,et al.MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.PLoS Genet,2012,8:e1002751
23 Deng L,Shang L,Bai S,et al.MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.Cancer Res,2014,74:6648-6660
24 Ginestier C,Liu S,Diebel M E,et al.CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts.J Clin Invest,2010,120:485-497
25 Liu S,Ginestier C,Ou S J,et al.Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks.Cancer Res,2011,71:614-624